Levodopa polymeric conjugates, formulations thereof, and their uses for the treatment of parkinson&#39;s disease

ABSTRACT

Compounds of formula I: or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof, wherein: R1 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that the carbonyl group is linked to R1 through an ester, amide, carbonate or carbamate bond; R2 is hydrogen, or —(C═O)Rs wherein R5 is a C1-3 straight or branched chain alkyl group; and R3 and R4 are independently selected from hydrogen, C1-3 straight or branched chain alkyl group, or —(C=0)Re wherein R6 is —(O—CH2—CH2)n—OCH3 or a C1-3 straight or branched chain alkyl group, and n is 1 to 5. The compositions are useful for the treatment of Parkinson&#39;s disease when administered alone or in combination with carbidopa and/or entacapone.

CROSS REFERENCE TO RELATED PATENT APPLICATION

This application claims priority to provisional U.S. Application No.62/868,134 filed Jun. 28, 2019, the contents of which are hereinincorporated by reference in their entirety.

FIELD OF INVENTION

The present invention relates to polymer conjugates of levodopa and itsprodrugs, and polymeric nanoparticle/microparticle formulations of thepolymer conjugates. These compounds and compositions are useful for thetreatment of Parkinson's disease.

BACKGROUND OF THE INVENTION

Levodopa is the common name for(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid, an

aromatic amino acid derivatives which is the main source of dopamine. Inhuman and in other animals, levodopa is synthesized from amino acidL-tyrosine and serves as the precursor in the synthesis ofneurotransmitters dopamine, norepinephrine (noradrenaline), andepinephrine (adrenaline), which are collectively known ascatecholamines.

Parkinson's disease (PD) is a progressive neurodegenerative disease thataffects approximately 1-2% of the population above the age of sixty.Symptoms include resting tremor, rigidity, slowness of movement andpostural instability caused by selective degeneration of dopaminergicneurons in the substantia nigra leading to disruption of thenigrostriatal pathway and decreased striatal dopamine levels. Olanow etal., Neurology. 2009; 72(21 Suppl 4):S1-136.

The efficacy of high dose levodopa (3-16 g/day) in treating PD was firstreported in 1969 (Cotzias et al., N. Engl. J. Med. 1969; 280(7):337-345;Yahr et al., Arch. Neurol. 1969; 21(4):343-354). The United States Foodand Drug Administration (“FDA”) approved levodopa for treatment for PDin 1970. Levodopa, unlike dopamine can cross the blood brain barrier(BBB) and is converted to dopamine in the central nervous system as wellas in the peripheral circulation. Most commonly, levodopa is used as adopamine replacement agent for the treatment of PD and is particularlyeffective in controlling the bradykinetic symptoms that are apparent inPD. Levodopa is recommended for symptomatic treatment of all stages ofParkinson's disease and is given multiple times every day by oral route.Levodopa is commonly administered with carbidopa, a dopaminedecarboxylase inhibitor, to decrease the amount of levodopa that isconverted to dopamine in the periphery. This combination therapy allowsfor more levodopa to cross the BBB. Once converted to dopamine, itactivates the postsynaptic dopaminergic receptors and compensates forthe decrease in endogenous dopamine.

Levodopa is absorbed in the small bowel and 95% of an administered oraldose is pre-systemically decarboxylated to dopamine by the aromaticL-amino acid decarboxylase (AADC) enzyme in the stomach, lumen of theintestine, kidney, and liver. Levodopa may also be methoxylated by thehepatic catechol-O-methyltransferase (COMT) enzyme system to3-Omethyldopa (3-OMD), which cannot be converted to central dopamine.Therefore, only a small portion of the oral dose of levodopa istransported across the BBB into the central nervous system (CNS) whereit is converted to the neurotransmitter dopamine by the brain's AADCenzyme. Dopamine is further converted to sulfated or glucuronidatedmetabolites, and homovanillic acid through various metabolic processes.The primary metabolites of levodopa are 3,4-dihydroxyphenylacetic acid(13-47%) and homovanillic acid (23-39%).

Because gastric AADC and COMT enzymes degrade levodopa, the drug isgiven with:

-   -   i) a peripheral dopamine decarboxylase inhibitors (carbidopa),        without which 90% of levodopa is metabolized in the gut wall,        and    -   ii) a COMT inhibitor (entacapone), which prevents peripheral        loss of levodopa about a 5%.

Inhibitors of AADC and COMT inhibit decarboxylation of levodopa in thestomach and periphery, making more levodopa available for transportacross the BBB to increase the dopamine content of the brain. Carbidopareduces the amount of levodopa required to produce a given response by75% when administered with levodopa. Co-administered withlevodopa/carbidopa, a 200 mg dose of entacapone increases levodopaplasma exposure by 35-40%.

Plasma half-life of levodopa alone is about fifty (50) minutes. Whenadministered along with carbidopa (Sinemet® and Sinemet® CR 50-200),that half-life is increased to 1.5 hours (Sinemet® label, NDA17555). Thetime to reach peak plasma concentration (T_(max)) was about 0.5 hoursfor Sinemet® and 2 hours for Sinemet® CR, the peak plasma concentration(C_(max)) was 1151 ng/mL vs. 3256 ng/mL for Sinemet® vs Sinemet® CR(Sinemet® CR label, NDA 019856). Following administration of Stalevo®(carbidopa, levodopa and entacapone combination, 37.5/150/200 mg), thet_(max) is about 1.5 hours and C_(max) is 1270±329 ng/mL (STALEVO®label, NDA 21485).

Common side effects of levodopa include nausea, vomiting, dry mouth,loss of appetite, heartburn, diarrhea, constipation, dizziness, musclepain, numbness or tingly feeling and trouble sleeping. Serious sideeffects include mood changes, increased eye blinking/twitching andworsening of involuntary movements/spasms. Motor fluctuations, includingdyskinesia and abnormal involuntary movements, are closely linked to thepharmacokinetics of levodopa, its irregular uptake, short half-life, lowbioavailability and marked fluctuations in plasma concentrations.LeWitt, Mov. Disord. 2015; 30(1):64-72; Tambasco et al., CurrNeuropharmacol. 2018; 16(8):1239-1252.

Development of dyskinesia can be avoided by using lower doses oflevodopa and by maintaining steady dopamine levels. Research is ongoingto find a delivery route for levodopa to achieve continuous dopaminergicstimulation. An intrajejunal infusion developed by Abbvie (Duopa®) isgiven by continuous infusion for the treatment of motor fluctuations inpatients with advanced Parkinson's disease approved by FDA in 2015. Alevodopa inhalation powder, Inbrija® by Acorda Therapeutics, Inc., wasapproved by the FDA in 2018. Some other formulations for continuoussubcutaneous (SC) infusion, such as ABBV-951 (Abbvie) and ND6012(Neuroderm/Mitsubishi Tanabe) are under development.

Levodopa has been modified to water soluble esters as well as amidederivatives for better brain uptake. Since there are three types ofactive functional groups in Levodopa to modify as prodrug derivatives,many prodrugs are reported. There are two benzylic hydroxyl groups at3,4-position, one amine group at 2-position and one active carboxylgroup at the terminal. The two hydroxyl groups of levodopa can bemodified to ester derivatives. The methylester of Levodopa (Levomet®) isalready in the market. However, the ethyl ester derivatives(Etilevodopa, TV-1203) was found to be less efficacious than Levodopa inPhase III clinical trials.

SUMMARY OF THE INVENTION

The invention provides certain polymer conjugates of levodopa and itsprodrugs with linear, branched and globular biocompatible polymers.These compounds offer sustained-release properties compared to freelevodopa which has a very short half-life. The invention also providesnanoparticle/microparticle formulations of polymer conjugates oflevodopa and its prodrugs using biocompatible pharmaceuticallyacceptable polymers. The compounds and compositions of the inventionprovide improved bioavailability and reduce the frequency of dosing andtotal dosage of levodopa, thereby improving the side effect profile oflevodopa, used alone or in combination with carbidopa and/or entacapone.

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof,wherein:

-   -   R₁ is a pharmaceutically acceptable polymeric moiety comprising        a pharmaceutically acceptable polymer chain such that the        carbonyl group is linked to R₁ through an ester, amide,        carbonate or carbamate bond;    -   R₂ is hydrogen, or —(C═O)R₅ wherein R₅ is a C₁₋₃ straight or        branched chain alkyl group; and    -   R₃ and R₄ are independently selected from hydrogen, C₁₋₃        straight or branched chain alkyl group, or —(C═O)R₆ wherein R₆        is —(O—CH₂—CH₂)_(n)—OCH₃ or a C₁₋₃ straight or branched chain        alkyl group, and n is 1 to 5.

Yet other embodiments of the present invention provide a pharmaceuticalcomposition comprising micro or nano particles comprising:

-   -   a pharmaceutically effective amount of the compound of formula        I; and    -   a second pharmaceutically acceptable polymer,

wherein the compound of formula I is encapsulated in the secondpharmaceutically acceptable polymer. Pharmaceutically acceptablepolymers used in the present invention may be linear, branched orglobular.

In some embodiments of the invention, the pharmaceutically acceptablepolymer and/or the second pharmaceutically acceptable polymer isindependently selected from the group consisting of polyethylene glycol(PEG), poly(glycolide) (PGA), poly(lactide) (PLA), poly(caprolactone),poly(lactide-co-caprolactone), poly(lactide-co-glycolide) (PLGA), andpoly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol)(PVA), poly(ethyleneimine), poly(malic acid), poly(L-lysine),poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins,hydroxyethylstarch, polysialic acid, polyacetals,N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine)dendrimers, and mixtures, combinations and copolymers thereof. In someembodiments of the invention, the pharmaceutically acceptable polymerand/or the second pharmaceutically acceptable polymer used forencapsulation is selected from the group consisting of PLA, PGA, PLGA,PVA, and combinations thereof in different proportions.

Certain embodiments of the invention provide compositions comprising apharmaceutically effective amount of the compound formula I and one ormore pharmaceutically acceptable carriers or excipients. In particular,castor oil or its derivatives may be used as an excipient. In someembodiments, the compositions are in the form of liposomes or micellesusing pharmaceutically acceptable amphiphilic compounds.

In certain embodiments of the invention, the micro or nano particlescompositions comprising polymer encapsulated compound of formula Ifurther comprise one or more pharmaceutically acceptable carriers orexcipients.

The compositions of the invention are useful for treatment of PD. Inparticular, the compositions are useful for the same treatments aslevodopa, used alone or in combination with carbidopa and/or entacapone,such as indications of levodopa alone or in combination with carbidopaand/or entacapone approved by USFDA or medicine regulatory agencies ofother countries.

In some embodiments, the compositions of the invention may beadministered by a parenteral route, such as intravenously,intramuscularly, intraperitoneally, or subcutaneously. In certain otherembodiments, the compositions of the invention may be administeredtopically, such as in the form of transdermal patches, creams, foams,gels, lotions, ointments, sprays, and eye drops that are appliedepicutaneously, applied to the conjunctiva or through inhalation.

In some embodiments, the compositions of the invention may beadministered once daily, or twice or thrice weekly. In otherembodiments, the compositions of the invention may be administered onceweekly, biweekly, or once monthly.

The compositions of the invention offer improved chemical andpharmaceutical properties, such as superior pharmacokinetic properties,compared to levodopa and require substantially reduced dosage to achievetherapeutic plasma concentration due to the structure of the compound offormula I, the nature of the compositions, and/or the mode ofadministration. The compositions of the invention reduce adverse eventsand variability in pharmacokinetics.

DETAILED DESCRIPTION

The prodrug of levodopa are obtained by using suitable chemical moietieswhich mask one or both reactive hydroxyl groups in the phenyl ringand/or the amine group of levodopa. In some embodiments, 0-diacetylderivatives or a short poly ethylene glycol (PEG) unit (repeating unitn=1-5) at 3 and 4 position of levodopa can be employed generating anester bond which is eventually converted to free Levodopa in the bodysystem. The two hydroxyl groups can also be converted to 0-methoxygroups for prolonged duration of action. It has been established thatthe amide prodrug of Levodopa in the form of acetamide in which theamine group is converted to acetamide has better C_(max), t_(max) andAUC (the area under the curve describing the variation of a drugconcentration in blood plasma as a function of time) as compared toLevodopa upon systemic administration (Jiang et al., J. Pharm. Biomed.Anal. 2010; 53:751-754). So, an N-acetylation reaction can be done withlevodopa to employ an acetamide group for improved efficacy. It is worthnoting here that, in the majority of prodrug formulations of levodopa,the C_(max), AUC and t_(max) values in the plasma are known. It is notnecessary that a better C_(max) value in plasma of a particular prodrugformulation has better brain uptake. It has been proven that even ifthere is no difference in C_(max) and t_(max) in plasma, an elevatedamount of dopamine was observed in the brain with such prodrugs ascompared to Levodopa (Ishikura et al., Int. J. Pharm. 1995; 116:51-63).

An in vivo cleavable bond is generated with the carboxylic acidfunctional group of levodopa to a biocompatible polymer so that thepolymer allows the levodopa to circulate in blood plasma for longer timewithout clearance. It also reduces the chances of peripheral degradationof levodopa to dopamine by AADC and COMT enzymes, thereby increasing thesubsequent availability of levodopa in the brain. The conjugatedcompound of formula I provides sustained plasma levels of levodopa withincreased delivery of levodopa to the brain, resulting in improvedefficacy.

Pharmaceutically acceptable polymers used in the present invention maybe non-toxic, non-immunogenic, non-antigenic, highly soluble in waterand FDA (The Food and Drug Administration) approved. The covalentattachment of polymer to a drug can increase its hydrodynamic size (sizein solution), which prolongs its circulatory time by reducing renalclearance (Knop et al., Angew. Chemie Int. Ed. 2010; 49(36):6288-6308;Veronese et al., Drug Discov Today. 2005; 10(21):1451-1458; and Harriset al., Nat Rev Drug Discov. 2003; 2(3):214-221). The polymer conjugatecompounds of the invention and polymer-encapsulated compositions of theinvention have several advantages including increased bioavailability atlower doses; predictable drug-release profile over a defined period oftime following each administration; better patient compliance; ease ofapplication; improved systemic availability by avoidance of first-passmetabolism; reduced dosing frequency without compromising theeffectiveness of the treatment; decreased incidence of side effects; andoverall cost reduction of medical care.

Polymer conjugates of formula I may be prepared by methods known in theart, for example, Sk U H et al., Biomacromolecules. 2013; 14(3):801-810.Polymer-encapsulated micro/nano particles may be prepared by methodsknown in the art. For example, Han et al., Front Pharmacol. 2016; 7:185;Qutachi 0 et al., Acta Biomater. 2014; 10(12):5090-5098.

In some embodiments, the pharmaceutically acceptable polymer chain incompounds of formula I comprises 15-75 monomer units, 20-70 monomerunits, or 25-65 monomer units. In other embodiments, the polymer has amolecular weight in the range of 1 kDa to 75 kDa, 2 kDa to 60 kDa, or 3kDa to 50 kDa.

In certain other embodiments, the pharmaceutically acceptable polymerchain in the compound of formula I is a straight or branched chain PEGcomprising 4-120 monomer units, 4-75 monomer units, 4-50 monomer units,or 4-30 monomer units. In certain other embodiments, the polymer is astraight or branched chain PEG comprising 12-120 monomer units, 12-75monomer units, 12-75 monomer units, or 12-30 monomer units. In someother embodiments, the polymer chain is a straight or branched chain PEGcomprising 11-20 monomer units, 26-42 monomer units, 49-64 monomerunits, or 72-111 monomer units. In certain other embodiments, thepolymer chain is a straight or branched chain PEG having a molecularweight in the range of 0.4 kDa to 50 kDa, 0.5 kDa to 50 kDa, 0.8 kDa to50 kDa, or 1 kDa to 50 kDa.

The term “encapsulated” in the context of the present invention meanscoated by, covered by, or surrounded by, such that about 20% to about80% of the compound of formula I is enclosed/covered/coated by thepolymer.

In some embodiments, PLGA and mixture of PLGA with other polymers, suchas PLA, PGA and PVA, in different ratios are used to encapsulatecompounds of the invention to form microparticles. Due to its excellentbiocompatibility, PLGA is a pharmaceutically acceptable biodegradablepolymer widely used for encapsulation of a broad range of therapeuticagents including hydrophilic and hydrophobic small molecule drugs, DNA,and proteins. Other additives can be used to enhance the drug loadingand efficiency in PLGA microparticles, such as PEG, poly(orthoesters),chitosan, alginate, caffeic acid, hyaluronic acid etc. PLGA can be avarying composition of PLA and PGA with a ratio from 20 to 80% PGA inPLA and vice versa.

In some embodiments, the amount of compound of formula I in thecompositions of the invention is in the range of 100 mg to 2000 mgequivalent of levodopa administered once daily. Compositions comprising10-200 mg of carbidopa and/or 200-1600 mg of entacapone may be used incombination with the compositions of the invention for treatment of PD.In some embodiments, compositions of the invention may include carbidopaand/or entacapone in addition to the compound of formula I. The amountof carbidopa co-administered with levodopa may be in a ratio of 1:10 to1:4 with respect to the amount of levodopa. Entacapone may beco-administered with levodopa in a dose of 200 mg and the dosagerepeated as required. Carbidopa in an amount of 10 mg to 200 mg/dayand/or entacapone in an amount of 200 mg to 1600 mg/day may beco-administered with the compounds or compositions of the invention.

In some embodiments, dosage forms of the composition of the inventionare adapted for administration to a patient parenterally, includingsubcutaneous, intramuscular, intraperitoneal, intravenous or intradermalinjections. In other embodiments, the composition may be administered asa depot. Upon parenteral injection of levodopa polymer conjugates offormula I, enzymatic cleavage may occur generating levodopa and/or itsprodrugs, and the respective polymer used in the conjugation.

In some embodiment, the compositions of the invention further compriseone or more pharmaceutically effective carriers or excipients.Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents.

The compositions may be presented in unit-dose or multi-dose containers,for example, sealed ampules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules, and tablets.

EXAMPLES

a) Preparation of Polymer Conjugates of Formula I

Levodopa may be prepared by methods known in the art or obtained fromcommercial sources. All prodrug of Levodopa (ester at 3,4-position andamide at 2-position) may also be prepared by methods known in the art.

Dissolve levodopa or its prodrug in anhydrous dimethylformamide (DMF)under nitrogen atmosphere. Add:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) andDimethylamino) pyridine (DMAP) dissolved in DMF to the reaction mixtureand stir the reaction mixture for 30 minutes. Add a calculated amount oflinear, branched PEG or any other carboxylate-functionalized globularpolymer dissolved in DMF to the reaction mixture and stir the reactionmixture for 2 days under nitrogen atmosphere. Evaporate the solvent anddialyze the resulting reaction mixture for 24 hours using dialysismembrane (MWCO 1 kDa) and then with water. Lyophilize the resultingwater to get the final levodopa polymer conjugates. Check the purity ofthe conjugate by reverse-phase high performance liquid chromatography(HPLC) and characterize/calculate the loading of the polymeric conjugateby proton nuclear magnetic resonance (NMR), and matrix assisted laserdesorption/ionization time-of-flight (MALDI-TOF) mass spectroscopy.

b) Preparation of Microparticles of Compound of Formula I

Nanoprecipitation technique is used for the preparation of the levodopamicroparticles. Briefly, either levodopa or levodopa prodrug and apolymer (e.g., PLGA) are dissolved in a suitable solvent (e.g.,dichloromethane) in different ratios, the mixture being subjected tosonication for 5-10 minutes to achieve dissolution, if required.Dissolve a hydrophilic non-ionic surfactant (for example a triblockcopolymer), such as Pluronic F127, in 50 mL of deionized water and addthe levodopa/PLGA solution dropwise using a syringe with a flow rate of1 mL/10 min with stirring at varying speed. Centrifuge, and lyophilizethe obtained nanosuspension with cryoprotectant (e.g., 2% sucrose).Characterize the microparticle with scanning electron microscopy (SEM),differential scanning calorimetry (DSC) and X-Ray diffraction (XRD).

1. A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof,wherein: R₁ is a pharmaceutically acceptable polymeric moiety comprisinga pharmaceutically acceptable polymer chain such that the carbonyl groupis linked to R₁ through an ester, amide, carbonate or carbamate bond; R₂is hydrogen, or —(C═O)R₅ wherein R₅ is a C₁₋₃ straight or branched chainalkyl group; and R₃ and R₄ are independently selected from hydrogen,C₁₋₃ straight or branched chain alkyl group, or —(C═O)R₆ wherein R₆ is—(O—CH₂—CH₂)_(n)—OCH₃ or a C₁₋₃ straight or branched chain alkyl group,and n is 1 to
 5. 2. The compound of claim 2, wherein thepharmaceutically acceptable polymer chain comprising the polymericmoiety R₁ is selected from the group consisting of polyethylene glycol,poly(glycolide), poly(lactide), poly(caprolactone),poly(lactide-co-caprolactone), poly(lactide-co-glycolide), andpoly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol),poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamicacid), and poly ((N-hydroxyalkyl)glutamine), dextrins,hydroxyethylstarch, polysialic acid, polyacetals,N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine)dendrimers, and mixtures, combinations and copolymers thereof.
 3. Acomposition comprising a pharmaceutically effective amount of thecompound of claim 1 and one or more pharmaceutically acceptable carriersor excipients.
 4. The composition of claim 3, wherein the composition isinjectable, inhalable, or topical.
 5. The composition according to claim3, wherein the composition is in the form of liposomes or micelles. 6.The composition according to claim 3, wherein the pharmaceuticallyacceptable carrier is castor oil or a derivative thereof.
 7. Apharmaceutical composition comprising micro or nano particlescomprising: a pharmaceutically effective amount of the compound offormula I; and a second pharmaceutically acceptable polymer, wherein thecompound of formula I is encapsulated in the second pharmaceuticallyacceptable polymer.
 8. The pharmaceutical composition according to claim7, wherein the second pharmaceutically acceptable polymer is selectedfrom the group consisting of polyethylene glycol, poly(glycolide),poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone),poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malicacid), poly(L-lysine), poly(L-glutamic acid), and poly((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialicacid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer,poly(amido amine) dendrimers, and mixtures, combinations and copolymersthereof.
 9. The pharmaceutical composition according to claim 8, whereinthe composition further comprises one or more pharmaceuticallyacceptable carriers or excipients.
 10. The composition of claim 9,wherein the composition is injectable, inhalable, or topical.
 11. Amethod for treating Parkinson's disease comprising administering thecomposition according to claim
 3. 12. The method according to claim 11,wherein the composition is administered intravenously, intramuscularly,intraperitoneally, or subcutaneously.
 13. The method according to claim11, wherein the composition is co-administered with carbidopa and/orentacapone.
 14. The method according to claim 12, wherein thecomposition is administered once daily.
 15. The method according toclaim 12, wherein the composition is administered twice weekly, thriceweekly, once weekly or biweekly.
 16. The method according to claim 12,wherein the composition is administered once monthly.
 17. A method fortreating Parkinson's disease comprising administering thecomposition-according to claim
 7. 18. The method according to claim 17,wherein the composition is co-administered with carbidopa and/orentacapone.
 19. The method according to claim 17, wherein thecomposition is administered intravenously, intramuscularly,intraperitoneally, or subcutaneously.
 20. The method according to claim17, wherein the composition is administered once daily, twice weekly,thrice weekly, once weekly, biweekly, or once monthly. 21-23. (canceled)